Study Identifies Caffeic Acid Induced AMPK-α2 Activity Behind the Fat Burning, Insulin-Sensitizing & Life-Extending Effects of Coffee. Plus: Why Creatine & Coffee Don't Mix!

Image 1: I've got news for you: Real coffee does not come in brown sterophome cups ;-)

Ever since Starbucks came out with the "McDonald's version" of what used to be the drink of the popes and kings, coffee has gotten sort of a bad reputation. It is supposed to "burn out your adrenal glands" (I bet most people who support this hypothesis don't even know where the adrenal glands are situated), derive you of  vital nutrients and water, reduce insulin sensitivity, give you palpitations and high blood pressure, ... I guess, you know the whole litany. If we take a closer look at the contemporary scientific consensus, many of these arguments against your 2-3 cups of coffee per day lack any scientifically verified basis. Others apply only if you (ab-)use the uber-potent high-caffeine, high sugar, low polyphenol Starbucks brew as "rocket fuel" on your mission not to mars, but to your first (or next?) heart attack.

Live longer, live leaner and live diabetes-free with...coffee!

I guess, some of you will probably remember my pre-Christmas blogpost on the "Anti-Diabesity Effects of Coffee", in which I elaborated on the results of a recently published paper by Matsuda et al. who observed significant reductions in weight gain in rodents receiving either diluted coffee or pure caffeine in addition to a fattening high fat (+high carb) diet. Contrary to the body weight gain, which was ameliorated about equally effective by both treatments, the "whole coffee" treatment had a much more pronounced effect on the particularly unhealthy visceral fat in the epididymal area (cf. previous news, figure 2).

Figure 1: Molecular structure of chlorogenic and caffeic acid, two of the major phenolic compounds in coffee beans (adapted from Tsuda. 2012)

Although these results clearly indicate that there is more to coffee than the world's most popular recreational drug, caffeine, they cannot answer the question what exactly this "more" would be. The most likely candidates obviously are the two major plant phenols in coffee beans, caffeic acid and its ester, cholorogenic acid (cf. figure 1). Both, caffeic, as well as cholorogenic acid have already been studied for their antihyperglycemic (=blood glucose lowering) effects in animal models (e.g. Rodriguez de Sotillo. 2002; Bassoli 2008), but the molecular mechanism by which they perform their blood sugar reducing magic had not been fully elucidated until Satoshi Tsuda and his colleagues from the Laboratory of Sports and Exercise Medicine at the Graduate School of Human and Environmental Studies of the University of Kyoto in Japan conducted an experiment which identified the AMPK-pathway about which you have already learned so much, here at the SuppVersity, as one, if not the underlying cause of the beneficial health effects of coffee.

In view of the fact that cacao, just like coffee contains both chlorogenic and caffeic acid (Duke. 2000), it is almost certain that the health benefits which have been ascribed to the consumption of phenol rich dark chocolate within the last couple of years can be traced back to increases in skeletal muscle AMPK-phosphorylation, as well.

To prove their hypothesis that caffeic acid and / or chlorogenic acid act directly on the AMPK-pathway in skeletal muscle,  the scientists incubated isolated rat epitrochlearis muscles with different amounts of the coffee phenols and measured the phosphorylation of AMPKα Thr¹⁷² and ACC Ser⁷⁹

Figure 2: Relative AMPK-phosphorylation in isolated rat epitrochlearis muscles in response to incubation with 0.01, 0.1 and 1mM of chologenic and caffeic acid (left); relative increase in AMPK-phosophorylation after incubation with 1mM of caffeic acid for 5, 15, 30 and 60 min (right; data adapted from Tsuda. 2012)

As you can see, caffeic acid, but not chlorogenic acid lead to dose- and time-dependent increase in skeletal muscle AMPK-phosphorylation (cf. figure 2). A similar response was observedfor its downstream target (data not shown in figure 2), Acetyl-CoA carboxylase (ACC), an enzyme that is directly involved in the regulation of mitochondrial fatty acid oxidation.

Figure 3: Relative increase in AMPK isoform phosophorylation (left) and increase in glucose transport measured with 3O-methyl-glucose as a marker (right) in skeletal muscle of rats after incubation with 1mM of caffeic acid for 30 min ( data adapted from Tsuda. 2012)

And while it does not come as a surprise that the increase in AMPK went hand in hand with the previously observed increase in glucose uptake the underlying mechanisms of which the scientists tried to uncover (cf. figure 3), it is of particular importance for physical culturists and anybody else who is interested to burn fat, while maintaining / building muscle that this effect was mediated by the alpha 2, not the alpha 1 isoform of AMPK. As I hope those of you who have been following my dissertations on AMPK in the Intermittent Thought (Part 1, Part 2, Part 3) will be aware of, the former, i.e. AMPK-alpha-2 is also expressed in response to exercise and does not reduce muscle protein synthesis by compromising the mTOR response (note: due to the isoform-specificity of caffeic could be called a true exercise mimetic).

Figure 4: Relative amounts of ATP and phosphocreatine (PCr) and phosphorylated AKT in skeletal muscle after incubation with 1mM of caffeic acid for 30 min (data adapted from Tsuda. 2012)

That you do not have to be afraid of losing muscle, if you ramp up your skeletal muscle AMPK expression by caffeic acid, is also supported by the absence of any detrimental effects on skeletal muscle protein kinase B (AKT) expression and the adenosin-triphosphate (ATP) levels in the skeletal muscle samples (cf. figure 4). What is intriguing, though, is the statistically significant decrease in the amount of phosphocreatine, a phosphorylated creatine molecule your muscle (and brain) tissue uses as a rapidly mobilizable energy reserve.

Caffeic acid won't decrease protein synthesis, but could reduce the effectiveness of creatine

And while Tsuda et al. mention the detrimental effect caffeic acid exerts on intra-muscular phosphocreatine stores in the discussion of the results, they are not able fully explain this observation which reminds me of the old "myth" that the caffeine in coffee would compromise the beneficial effects of creatine supplementation... I guess we have just found why some studies did in fact support this hypothesis. If the caffeic acid induced increase in AMPK-phosphorylation goes hand in hand with a reduction in the amount of stored creatine phosphate (PCr), this could mean that you would need more creatine to achieve and maintain "maximal" levels of this high-performance energy reserve.

As you can see, it is always the same, with every question we answer a new one arises. What did Socrates say? Yeah: "I know that I know nothing!" I suppose this is a good concluding word for today's blogpost. Come back tomorrow if you want to know what else you do not know ;-)